Deep analysis of total serum N-glycome suggests glyco-signatures for phospholipase A2 receptor 1-related idiopathic membranous nephropathy diagnosis

IF 2.8 2区 生物学 Q2 BIOCHEMICAL RESEARCH METHODS
Yan Cai , Weifu Ren , Siqian Li , Rijing Liao , Qi Bian
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Abstract

Idiopathic membranous nephropathy (IMN) is an antibody-mediated and kidney-specific autoimmune disease, with the antigen phospholipase A2 receptor 1 (PLA2R1) accounting for approximately 70% of IMN cases. Although a variety of new podocyte target antigens and their autoantibodies have been identified, they are still of limited diagnostic and therapeutic value due to lack of high specificity and sensitivity. N-glycans play vital roles in renal system and their pathobiological relevance has become increasingly recognized in many kidney diseases, but not fully explored in IMN. To find possible glyco-signatures for PLA2R1-related IMN diagnosis, we herein established a comprehensive workflow for total serum N-glycome analysis based on our recently developed mass spectrometry (MS)-based N-glycan purification method, named Ultrafast Glycoprotein Immobilization for Glycan extraction (UltraGIG). A total of 191 N-glycans were identified from IMN patients, representing the largest N-glycome dataset in IMN. Compared to healthy controls, up-regulation of sialylation and core-fucosylation as well as down-regulation of galactosylation were observed in PLA2R1-positive IMN patients, and up-regulation of hyper-galactosylation was specific for PLA2R1-negative IMN patients. A six-glycan marker panel consisting of H4N3S1, H4N3F1, H6N4S2, H6H5F1S2, H6N5 and H6N6F1S1, was proposed to aid in the accurate diagnosis of PLA2R1-related IMN, which provided new insights into IMN biomarker study.

Significance

PLA2R1-related IMN is a kidney-specific autoimmune disease with a high risk of developing end-stage renal disease (ESRD) and even kidney failure. Current biomarkers are still of limited diagnostic and therapeutic value due to lack of high specificity and sensitivity. An in-depth MS analysis of total serum N-glycome of PLA2R1-related IMN patients was conducted for the first time. We generated the largest dataset of serum N-glycome for IMN to date, and proposed a novel six-glycan marker panel that may help the accurate diagnosis of PLA2R1-related IMN.

Abstract Image

对血清总 N-糖蛋白的深入分析为磷脂酶 A2 受体 1 相关特发性膜性肾病的诊断提供了糖蛋白特征。
特发性膜性肾病(IMN)是一种抗体介导的肾脏特异性自身免疫性疾病,抗原磷脂酶 A2 受体 1(PLA2R1)约占 IMN 病例的 70%。虽然已经发现了多种新的荚膜目标抗原及其自身抗体,但由于缺乏高度特异性和敏感性,其诊断和治疗价值仍然有限。N-聚糖在肾脏系统中发挥着重要作用,其在许多肾脏疾病中的病理生物学相关性已被越来越多的人所认识,但在 IMN 中还没有得到充分探讨。为了寻找可能用于 PLA2R1 相关 IMN 诊断的糖特征,我们在此建立了一套全面的工作流程,基于我们最近开发的基于质谱(MS)的 N-糖纯化方法(名为 "超快糖蛋白固定化糖提取(UltraGIG)")进行血清 N-糖总蛋白分析。从 IMN 患者身上共鉴定出 191 个 N-聚糖,这是 IMN 中最大的 N-聚糖数据集。与健康对照组相比,在 PLA2R1 阳性的 IMN 患者中观察到糖基化和核心-岩藻糖基化的上调以及半乳糖基化的下调,而高半乳糖基化的上调是 PLA2R1 阴性的 IMN 患者所特有的。该研究提出了一个由 H4N3S1、H4N3F1、H6N4S2、H6H5F1S2、H6N5 和 H6N6F1S1 组成的六聚糖标记物面板,以帮助准确诊断 PLA2R1 相关 IMN,这为 IMN 生物标记物研究提供了新见解。意义:与 PLA2R1 相关的 IMN 是一种肾脏特异性自身免疫性疾病,具有发展为终末期肾病(ESRD)甚至肾衰竭的高风险。由于缺乏高特异性和灵敏度,目前的生物标记物诊断和治疗价值仍然有限。我们首次对 PLA2R1 相关 IMN 患者的血清总 N-糖蛋白进行了深入的 MS 分析。我们建立了迄今为止最大的IMN血清N-糖蛋白数据集,并提出了一种新型的六聚糖标记物面板,它可能有助于准确诊断与PLA2R1相关的IMN。
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来源期刊
Journal of proteomics
Journal of proteomics 生物-生化研究方法
CiteScore
7.10
自引率
3.00%
发文量
227
审稿时长
73 days
期刊介绍: Journal of Proteomics is aimed at protein scientists and analytical chemists in the field of proteomics, biomarker discovery, protein analytics, plant proteomics, microbial and animal proteomics, human studies, tissue imaging by mass spectrometry, non-conventional and non-model organism proteomics, and protein bioinformatics. The journal welcomes papers in new and upcoming areas such as metabolomics, genomics, systems biology, toxicogenomics, pharmacoproteomics. Journal of Proteomics unifies both fundamental scientists and clinicians, and includes translational research. Suggestions for reviews, webinars and thematic issues are welcome.
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